The localized or targeted delivery of chemotherapeutics has been exploited in recent trends to limit the indiscriminate toxicities to normal tissues associated with chemotherapy. In general, these toxicities are often the dose limiting factors in reaching effective therapeutics in cancerous tissues because they are often life threatening.
Paclitaxel (“PTX”), the first of a new class of microtubule stabilizing agents, is recognized as an effective chemotherapeutic for a wide variety of solid tumors (Ajani et al., “Phase II Study of Taxol in Patients with Advanced Gastric Carcinoma,” Cancer J. Sci. Am., 4(4), 269-274 (1998); and Rogers, “Taxol: A Promising New Drug of the '90s,” Oncol. Nurs. Forum, 20(10), 1483-1489 (1993), which are hereby incorporated by reference). Clinical application of this highly effective drug in the treatment of cancer is limited because of its poor aqueous solubility (0.6 mM) and poor oral bioavailability (Matthew Suffness, ed., Taxol: Science and Applications, Boca Raton, Fla.: CAC Press LLC (1995), which is hereby incorporated by reference). To date, only two commercial formulations have been developed. The first formulation developed uses 1:1 mixture of Cremophor EL and ethanol to increase the solubility of paclitaxel (7 mM) administered intravenously (Tarr et al., “A New Parenteral Vehicle for the Administration of Some Poorly Soluble Anti-Cancer Drugs,” J. Parenteri. Technol., 41:31-33 (1987), which is hereby incorporated by reference). Cremophor may have serious adverse side effects including severe hypersensitivity reactions, neurotoxicity, nephrotoxicity, and hypotensive vasodilation (Chao et al., “Paclitaxel in a Novel Formulation Containing less Cremophor EL as First-Line Therapy for Advanced Breast Cancer: A Phase II Trial,” Invest. New Drugs, 23(2):171-177 (2005); Gelderblom et al., “Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation,” Eur. J. Cancer, 37(13):1590-1598 (2001); and Friedland et al., “Hypersensitivity Reactions from Taxol and Etoposide,” J. Natl. Cancer Inst., 85(24):2036 (1993) (“Friedland”), which are hereby incorporated by reference). In addition to solvent-associated toxicity, paclitaxel has many indiscriminate side effects that can be life threatening. These include nausea, vomiting, hypersensitivity, bone marrow depression, and arrhythmias (Friedland; Singla et al., “Paclitaxel and Its Formulations,” Int. J. Pharm., 235(1-2):179-192 (2002); and Rowinsky et al., “Neurotoxicity of Taxol,” J. Natl. Cancer Inst. Monogr. (15):107-115 (1993), which are hereby incorporated by reference). The newest addition to the commercial marketplace, ABRAXANE™., is an injectable suspension of albumin-bound paclitaxel nanoparticles (Ibrahim et al., “Phase I and Pharmacokinetic Study of ABI-007, a Cremophor-Free, Protein-Stabilized, Nanoparticle Formulation of Paclitaxel,” Clin. Cancer Res., 8(5):1038-1044 (2002); and Gradishar, “Albumin-Bound Paclitaxel: A Next-Generation Taxane,” Expert Opin. Pharmacother., 7(8):1041-1053 (2006), which are hereby incorporated by reference). However, bone marrow suppression is not only the dose dependant and dose limiting toxicity, but also neuropathy toxicity has been shown to be remarkably increased when compared to the traditional PTX formulation (Socinski, “Update on Nanoparticle Albumin-Bound Paclitaxel,” Clin. Adv. Hematol. Oncol., 4(10):745-746 (2006); and Lee Villano, J. et al., “Abraxane Induced Life-Threatening Toxicities with Metastatic Breast Cancer and Hepatic Insufficiency,” Invest. New Drugs, 24(5):455-456 (2006), which are hereby incorporated by reference).
Poor aqueous solubility has also limited the usefulness of other chemotherapeutic agents.
In view of the above, a need continues to exist for formulations for the delivery of paclitaxel, other taxanes, and other chemotherapeutic agents, and the present invention is directed, in part, to addressing this need.